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Dr. Channakeshava Sokke Umeshappa
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Dr. Clarus Leung
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Shirley Quach
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CAAIF-Immunodeficiency Canada Research Fellow in Immunodeficiency
Dr. Ori Scott
Elucidating pathophysiology of auto-inflammatory disease mechanisms
in the inborn error of immunity STAT1 gain-of-function
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STAT1 is a gene that plays a critical role in the immune response against infections, and in particular against viruses. Because STAT1 is such an important gene, its activity is tightly regulated in most healthy people. STAT1 gain-of-function (GOF) is a genetic primary immunodeficiency, which is caused by increased activity of STAT1. The most common symptoms in patients with STAT1 GOF is chronic fungal infections, which are typically not life threatening. However, some STAT1 GOF patients also develop severe symptoms, such as lethal viral infections, or severe autoimmunity/auto-inflammation. In this work, we will use a mouse model to study what causes such severe disease manifestations in STAT1 GOF. Importantly, STAT1 activity can be disrupted even in people who do not have STAT1 GOF. For this reason, by researching STAT1 GOF, we can learn a lot about the development of severe infections, autoimmunity or inflammation even in people without STAT1 GOF. Ori is thankful to the Canadian Allergy, Asthma, and Immunology Foundation and Immunodeficiency Canada for their support of this work.
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This award was jointly funded by CAAIF and Immunodeficiency Canada
Allergic Airways Disease Innovation Grant
Dr. Paul Forsythe
Pulmonary Neuroendocrine Cells as targets for gene therapy in
asthma
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This study focuses on specialized cells in the lung called Pulmonary Neuroendocrine Cells (PNEC). PNEC are found in the surface lining of the lung (epithelium) and are very rare (less than 1% of cells in the epithelium) but play an important role in detecting changes in the content of the air we breathe (oxygen levels, pollutants, bacteria), allowing the lungs to respond and maintain healthy function. PNEC are increased in number in asthmatics and recent studies, in mice, suggest that these cells play a key role in causing asthma and/or making asthma symptoms worse. Our own preliminary work shows that, when exposed to allergens, PNEC start expressing Calcitonin Gene Related Peptide (CGRP), a neuropeptide known to enhance airway inflammation. By modifying CGRP gene expression in PNEC we may be able to control the airway inflammation associated with asthma. We propose that PNEC are strong candidates for gene therapy delivered directly to the lungs as they are anatomically located at the branching points of airways, ideally placed to interact with inhaled substances. Our study will set out to determine if PNEC are suitable and meaningful targets for inhaled gene therapies. We have established a method to produce human PNEC from induced pluripotent stem cells; allowing us to study the biology of a cell that is too rare to isolate from human lung tissue. We will use these stem cell derived human PNEC to develop lipid nanoparticle delivered gene therapy that can supress gene expression and production of proinflammatory CGRP. We will then test the efficacy of PNEC targeted gene therapy in a preclinical model of asthma. If successful, this project will be the first stage in the development of an entirely new approach to treating asthma with the possibility of reducing disease burden in those who do not respond to current treatments.
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This award was jointly funded by AstraZeneca Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Allergic Airways Disease Innovation Grant
Dr. Bruce Mazer
Allergic Airways Disease Innovation Grant
Dr. Channakeshava Sokke Umeshappa
Development of a novel, targeted, cell-based immunotherapeutic drug for asthma
The overall objective of this proposal is to develop a cell-based immunotherapeutic drug of ground-breaking significance for severe asthma.
The proper functioning of the lungs is vital for life. In asthma, the airways get damaged, compromising optimal performance and well-being and, when severe, shortening lifespan. It affects both adults and children, and can be a life-long problem. Asthma is the most common long-term respiratory illness. Across Canada, approximately 1 in 3 people has asthma, and nearly 4 million Canadians are living with asthma.
There are only a few specific drugs, unlike we have for bacterial infections, for asthma, perhaps because of the complex immune mechanisms involved. Severe asthma is treated generally by non-specific immunosuppressants such as steroids that suppress the whole immune system that is otherwise necessary for defending our body. Consequently, steroid therapy can adversely affect our immune system, increasing the risk of lung infections.
Asthma is caused by small particles present in the environment called allergens. Certain white blood cells respond to these allergens, become dangerous and damage airways. We will develop a cell-based anti-asthma treatment, which will kill these harmful white blood cells that respond to allergens, a long-sought-after goal in severe asthma therapy. We will test our drug’s therapeutic efficacy and safety using a well-established animal model of asthma, which facilitates our subsequent clinical translation of this therapeutic platform. The research will be pursued with a leading-edge interdisciplinary team of established scientists, clinicians, and trainees spanning the spectrum of synthetic biology, bioinformatics, and immunology.
By restoring normal lung functions in a disease-specific manner, without causing general immune suppression, our treatment should prevent asthma patients from getting chronic breathing problems and secondary infections, making Canada and the World a healthier place to live.
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This award was jointly funded by AstraZeneca Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
CAAIF Research Fellowship in Immunology
Supported by Takeda Canda
Dr. Vanessa Polito
Phenotypic and genotypic characterization of hyper IgE immune dysregulation
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Abnormal functioning of the immune system, known as immune dysregulation, manifests in different ways. Patients can present with severe and recurrent infections, allergies, autoimmune disease, or malignancy. Allthough allergies are common, a subset of patients with severe allergies, known as atopic disease, may also have underlying abnormalities of their immune system. Atopic disease can be mediated by a specific antibody in the blood called IgE. A high level of IgE, as measured on a blood test, can be an indicator of atopy. In order to better understand this antibody's function, we are studying patients with high levels of IgE antibodies. We will collect data on their "phenotype" or the types of clinical problems they have. We will then perform genetic studies - known as whole exome sequencing. This will allow us to analyze the DNA building blocks, or genetic code, that may be causing these abnormally high levels of IgE antibodies and resulting immune dysregulation. We hope to characterize groups of patients by their phenotypes - for instance those that have infections, those those that have allergies, or those that are clinically well - and correlate this to the type of genetic changes they have in their DNA. The goal of this project is both to identify new genetic mutations causing these health problems, and to better diagnose and treat this group of patients. Ideally, we can better identify patients with this type of immune dysregulation to treat them more effectively.
Graduate Student Awards in Asthma
Harkiran Kooner
Are CT Mucus Plugs disrupted following two years of Benralizumab treatment in severe, eosinophilic asthma?
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Severe, eosinophilic asthma is characterized by airway inflammation and luminal obstruction that occurs as a result of eosinophils in the airways. These patients often report frequent exacerbations and reduced quality-of-life, despite treatment with high-dose medication. Airway mucus plug formation can be encouraged by mucin-eosinophil interactions in the airways and the associated symptoms and airway obstruction are not easily reversed using commonly prescribed asthma therapies. Benralizumab, an interleukin-5 biologic therapy, reduces airway eosinophilia. Thus, this research will investigate whether the elimination of airway eosinophils by benralizumab will alter the presence of mucus plugs, quantified via CT imaging, in the airways of asthma patients after two years of treatment. Based on previously published work, we hypothesize that severe asthma patients with a greater number of mucus plugs prior to treatment will have a greater improvement in quality-of-life and asthma control following benralizumab as a result of the disruption of mucus plugs in their airways. Confirmation of this concept using CT imaging immediately prior to and following two years of therapy will provide the foundation necessary for precision-medicine to target mucus occlusions in patients with poorly-controlled, eosinophilic asthma who do not find relief with traditional asthma therapies. Therefore, this project can identify patients with asthma whom would benefit most from biologic treatment, leading to significantly improved quality-of-life and asthma control in this subset of severe asthma patients.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Graduate Student Award in Asthma
Fang Fang Li
Uncovering viral determinants of asthma development by serological profiling
Worldwide prevalence of asthma has been increasing over the last decade, with higher rates recently observed in industrialized countries. The current leading theory best explaining the worldwide disparity is the hygiene hypothesis, which suggests that exposures to microorganisms during early childhood are essential to preventing immune-related conditions such as asthma by school-age. Supporting the hygiene hypothesis, several studies have demonstrated a protective effect against allergies and asthma in those exposed to Epstein-Barr virus, a common respiratory virus, in their childhood. However, recent research has also demonstrated that other common respiratory viruses, such as human rhinovirus and respiratory syncytial virus, can instead increase the risk of asthma development, thus challenging the hygiene hypothesis. Alongside recent work implicating viral gastroenteritis as another potential risk factor for asthma, we believe that all viral infections could potentially influence the risk of asthma development by school-age, though the direction is virus-dependent. This project aims to link together the complex relationships between asthma and viral infections in young Canadians using Canada’s largest birth cohort, the Canadian Healthy Infant Longitudinal Development (CHILD) study. By uncovering the combinations of viral infections influencing asthma outcome, we can direct new avenues of asthma research and ultimately design better strategies for the prevention and treatment of asthma.
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This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).